1. Field of the Invention
This invention relates to immunosuppressive agents and their use in transplantation therapy. In particular, the invention is directed to the use of cyclic AMP compounds, their nucleoside derivatives, and agonists thereof for suppressing graft rejection.
2. Background Art
Many human diseases are characterized by excessive or inappropriate immune responses. In transplantation, the immune system attacks major histocompatibility complex (MHC)-disparate donor tissue leading to graft rejection. In autoimmune disease, the immune system attacks normal tissues. In allergy, the immune system is hyperresponsive to otherwise harmless environmental antigens. It is now recognized that immunosuppressive therapy is appropriate for treating each of these disorders (Blood Reviews, 1995, 9:117-133).
There has been a phenomenal increase in the success of organ transplants since the 1950s, and transplantation has become the treatment of choice for end-stage renal and cardiac failure. A number of advances have recently been made in understanding immune regulation, and in the development and use of immunosuppressive therapies (Thomson, A. W. et al., Immunol.. Rev., 1993, 136:71-98; Allison, A. C. et al. eds, 1993, Ann. NY Acad. Sci. 696:1-419; Kahan, B. D., 1994, Therapeutic Immunol.. 1:33-44; Thomson, A. W., et al., eds., 1994, Immunosuppressive Drugs, London: Edward Arnold). Although the development of drugs such as cyclosporin A (CsA) and FK506 has led to substantial improvements in preventing graft rejection, especially over the first year (Sigal, N. H., et al, 1992, Ann. Rev. Immunol.. 10:519-560; Thomson, A. W., et al., 1994, Clin. Exp. Immunol.. 98:351-357), there are serious side effects associated with use, such as nephrotoxicity and neurotoxicity (Kahan, B. D., et al., 1985, Surgery 97:125). In addition, the widely used immunosuppressive drugs are not soluble or orally available in pill form, and require administration by injection.
Graft-versus-host disease (GVHD) occurs when genetically disparate lymphocytes are transferred into an immunologically compromised recipient incapable of rejecting the donor graft (Billingham, R. E. Harvey, Lect,, 1967, 62: 21-78; Nash, R. A. and Storb, R., Current Opinion in Immunology, 1996, 8: 674-680). Acute GVHD is a major and frequent complication of bone marrow transplantation (BMT) (Ferrara, J. L. M. et. al., Transplantation, 1989, 47: 50-54). Although T cells are clearly required for the induction of the disease in both clinical and animal models of BMT, natural killer (NK) cells have been implicated in target tissue damage (Ferrara, J. L. M. et. al., Transplantation, 1989, 47: 50-54; Ghayur, T. et. al., Transplantation, 1987, 44: 261-267; Nash, R. A. and Storb, R., Current Opinion in Immunology, 1996, 8: 674-680). Prevention of GVHD has been attempted most often with pharmacological immunosuppression. The most commonly used agents are cyclosporine-A (CsA), methrotrexate, prednisone and FK506 (Storb, R. et. al., New England Journal of Medicine, 1986, 314: 729-735; Storb, R. et. al., Blood, 1990, 76: 1037-1045; Nash, R. A. et. al., Blood, 1995, 85: 3746-3753). However, these agents have potential side effects, such as nephrotoxicity, increased hair growth on the body, and neurotoxicity (Kahan, B. D. et. al., Surgery, 1985, 97: 125; Fay, J. W. et. al., Blood, 1996, 87: 3514-3519). There is, therefore, a clinical need to provide new compounds for effective immunosuppression without these side effects and with greater ease of administration.